CYP2D6 activity in patients with metastatic breast cancer treated with single agent tamoxifen: results from ECOG-ACRIN E3108.

Purpose: In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes.

Patients and methods: Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20 mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3 month post registration plasma samples (Quest Diagnostics).

Results: From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86% (97/113) were white, 33% (30/113) Hispanic, 83% (92/113) postmenopausal. Samples were evaluable for CYP2D6 in 75% (85/113) of patients (2/85 PM, 27/85 IM, and 56/85 NM). Median PFS for PM and IM + NM was 12.9 months and 6.9 months, respectively. Median PFS was 11.1 and 13.8 months respectively for patients with low (≤ 15.5) and high (> 15.5) endoxifen concentrations (ng/ml).

Conclusion: We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS.

Trial id: NCT01124695 (registered May 14, 2010).